Breakthrough for prostate cancer

Two new therapies for advanced prostate cancer reflect the enthusiasm that doctors hold for the future treatment of this disease.

CANCER of the prostate (CaP) is the most common cancer (other than skin cancer) in males in Western countries. In the US, it has been estimated that about 200,000 men were diagnosed with CaP in 2009, with more than 27,000 dying from the disease.

The prevalence of CaP in Asian countries is rapidly increasing as a result of the increased consumption of Western-style meals (diet has been strongly implicated as a risk factor for CaP).

In Taiwan, currently, CaP is the third most common cancer in men, and the numbers affected are still on the rise.

The hope for advanced prostate cancer patients is even brighter when these innovative therapies are non-invasive and may just require taking a few pills per day. – AFP

A question of castration

Cancer of the prostate is an androgen-receptor dependent disease, and the treatment for advanced prostate cancer is androgen deprivation therapy (ADT), or in layman’s term, depriving the cancer of testosterone.

For decades, ADT has been the most effective and successful treatment for prostate cancer. However, in nearly all cases, the cancer eventually progresses after 12 to 48 months despite ADT, depending on how extensive the disease, host factors, and inherent tumour characteristics or biology.

The cancer invariably develops new tumour characteristics and clinical behaviours after treatment with ADT. This newly evolved cancer is known as castration-resistant prostate cancer (CRPC), which is inevitably fatal. The transformed and fiercer cancer thrives and spreads rapidly despite the body having very low testosterone levels.

The current treatment for CRPC is chemotherapy, using a standard docetoxel-based regime. However, the prognosis remains poor, and median survival with chemotherapy is less than two years.

There is currently no standard of care for patients who fail chemotherapy, and the results of all existing therapies are very poor.

This pathetic and pessimistic scene is going to change within the next few years. Over the past few months, the US Food and Drug Administration (FDA) has approved three new drugs for terminal stage CRPC, and two have already demonstrated the potential of extending patients’ lives.

Further, a whole host of revolutionary therapies, mainly oral medications, will come soon. Many of these new targeted or boutique drugs, which include denosumab, cabozantinib, MDV 3100, ARN-509, and TAIC-700, are in the late stages of development, and are near to final regulatory approvals.

We are certainly living in very exciting times where the bleak future of advanced castration-resistant prostate cancer patients are showered with optimistic rays of hope.

Becoming hormone refractory

How do prostate cancer cells evolve, grow, and spread rapidly despite very low testosterone levels in the body? Several things can result in this change:

· Genetic changes in the prostate cancer cells, or mutation resulting in more or different androgen receptors, result in the tumour thriving on very low levels of testosterone.

· The prostate cancer cells acquire the ability to produce their own testosterone from cholesterol molecules. This was certainly an unexpected discovery by medical researchers.

· The cancer cells develop mechanisms to evade detection by the body’s immune system, thus the body’s immune system is unable to recognise the tumour. The cancer cells can do this by creating changes that keep the immune killer cells in an immature state, allowing the tumour cells to spread throughout the body with impunity.

The recent launch of two innovative therapies for CRPC has brought about tremendous interest and excitement to urologists and oncologists worldwide. This is truly the beginning of many new effective therapies for end-stage prostate cancer patients, bringing realistic hope to these terminally-ill patients.

Two new drugs

Below are the two therapies recently approved by the FDA that have proven to increase patients’ survival:

· Provenge is the first FDA-approved immune-boosting treatment that prolongs the life of advanced prostate cancer patients. In pivotal clinical trials, the Provenge-treated patients lived significantly longer than men treated in the control group. A 22.5% reduction in the risk of death was recorded.

Treatment with Provenge, also known as Sipuleucel-T, involves removing a small quantity of patient immune cells in a specialised centre. These cells are sent to the company’s manufacturing facility. After about three days, the patient returns to the centre to receive an infusion of the boosted immune cells, which aim to kill off prostate cancer cells.

These newly boosted cells are also able to recruit other immune fighters or killer cells in eradicating prostate cancer cells. The entire Provenge treatment is repeated three times over a period of about four weeks.

The most common side effects that occur with Provenge treatment occurs one day after the infusion of the boosted immune cells. These side-effects include chills (7% of the patients), fever (23%), fatigue (16%), nausea (14%) and headache (11%). Most of these flu-like symptoms are temporary. In the clinical trials, less than 1% of the patients stopped treatment because of side effects.

The median survival benefit of Provenge therapy is about 4.1 months. About a third of the men in the pivotal trials were still alive three years after the treatment.

· The other breakthrough treatment for CRPC approved by the FDA about a month ago is Abiraterone. This is a pill with a low rate of side effects and has been shown to improve the life of CRPC patients who have failed all other treatments, including chemotherapies.

The oral medication is able to suppress androgen production in the adrenal gland, the testes, as well as in the prostate cancer cells. It is otherwise known as a true “de novo” androgen synthesis inhibitor, which practically wipes out all androgen manufacturing processes in the entire body of cancer prostate patients.

In clinical trials, patients were given 1,000mg (four pills) per day for a 28-day cycle in combination with prednisone 5mg. This regime has proven to be safe and effective in prolonging the life of CRPC patients.

There was a 35% reduction in the risk of death as compared with placebo plus prednisone, with a median survival of 14.8 months among patients who received abiraterone acetate plus prednisone, versus 10.9 months among patients who received placebo and prednisone.

The Abiraterone group of patients also show significant improvement in x-ray findings, a longer time to disease progression, and longer progression-free period. Side effects include hypertension, low potassium levels, and lower-limb swellings, are generally tolerable, and can be controlled with low dose prednisolone.

The Abiraterone research has enable medical scientists to understand in detail the biology involved in the progression of metastatic CRPC and this augurs well for researchers to develop more effective targeted approaches to further improve the outcome of treatment for CRPC patients.

Bright future

With the advent of truly effective therapies which can prolong survival of CRPC patients, the light at the end of the tunnel is ever brighter. The knowledge leading to the development of these two totally different therapies for CRPC has certainly opened up new pathways for the development of many more new targeted therapies.

There is every hope that the future management of CRPC or prostate cancer will follow the developmental paths of treating advanced testicular cancer, which was a fatal disease before the development of an effective chemotherapy regime. The early chemotherapy trials for advanced testicular cancer prolonged life by about four months, (like Provenge and Abiraterone). But today, more than 90% of all advanced testicular cancer cases are curable.

Testicular cancer is one of the few cancers that is considered totally curable and the patients go on to live a normal, full healthy life. In the coming decade, we will definitely see many more targeted therapies which could prolong lives. Using a combination of these therapies, which are proven to prolong survival, there is every hope that nearly all cases of prostate cancer at any stage may be totally curable.

The hope is even brighter when these innovative therapies are non-invasive and may just require taking a few pills per day.

These recent spectacular breakthroughs in treatment of CRPC have brought back memories of a dear friend and colleague who battled CRPC for a couple of years. We had tried practically every therapy available, including current hormonal and chemotherapies. He succumbed to the battle just weeks before the availability of these two FDA approved revolutionary therapies.

The battle against many cancers has taken centre stage. We are certainly racing against time to bring hope to the lives of patients who are unfortunate to have incurable cancer at this point in time.

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